- The skin is made up of two distinct layers: the epidermis and dermis. The outermost layer, the epidermis, is composed of cells called keratinocytes that undergo regulated cellular changes known as differentiation in order to produce a durable water- and germ-resistant barrier. The underlying dermis is composed of cells called fibroblasts that provide the collagen platform as well as the growth factors necessary for the regulated proliferation and differentiation of keratinocytes. The dermis also signals the epidermis to produce hair, sweat glands, and nails in their proper places. Dysfunction of the dermis is speculated to be a component of skin pathologies including wound healing disorders, some epidermal cancers, and skin aging. It appears there is an exchange of molecules between epidermis and dermis that is crucial to the function of both cellular layers. Very little is known about these molecules and how they perform their functions. One such molecule produced by keratinocytes that appears to regulate fibroblast function is parathyroid hormone related-protein (PTHrP). This proposal is based upon findings from a recently-generated transgenic mouse that lacks PTHrP. These mice have a severe skin disorder that may represent premature skin aging. On the basis of preliminary evidence contained within this proposal the following hypothesis is suggested: Keratinocyte-derived N-terminal PTHrP regulates epidermal differentiation by paracrine signaling mediated through classical PTH/PTHrP receptors expressed on dermal fibroblasts, resulting in the production of growth factors that influence the proliferation/differentiation of basal keratinocytes. This hypothesis will be tested in the following specific aims: 1) Determine PTHrP and PTH/PTHrP receptor expression in skin of fetal, neonatal, adult, and aged mice 2) Determine molecular and cellular mechanisms of PTHrP signaling in skin. 3) Determine the effect of N-terminal PTHrP on dermal fibroblast proliferation and function in vitro and in vivo.